Following our previous therapeutic success with cyclophosphamide (CP) in the treatment of Wegener's granulomatosis (WG), we have gone on to evaluate the safety and efficacy of methotrexate (MTX) as an alternative therapy in this disease in order to avoid the side effects of CP. Forty-two patients who did not have immediately life-threatening disease were studied. The median follow-up was 33.7 months. Weekly administration of MTX and prednisone resulted in remission of disease in 33/42 patients (78%). Nineteen of the 34 patients achieving remission experienced a relapse of disease. The estimated median time to relapse for all patients achieving remission was 29 months. Eighty percent of these relapses occurred in patients who had discontinued MTX or had reduced their dose to 15 mg/week or less. Thus, MTX plus prednisone may be an acceptable alternative form of therapy for selected patients with WG. As part of our continuing efforts to identify less toxic alternative treatments for WG and related diseases, we have initiated a phase I trial of lisofylline in the treatment of WG. Lisofylline is a methylxanthine derivative which functionally blocks pathways of IL-1beta and TNF-alpha signal transduction and has in vitro and in vivo antiinflammatory activity. Because blister studies performed here have demonstrated increased levels of the cytokines in patients with WG, lisofylline may be a useful therapy. Preliminary results suggest that lisofylline may have clinically significant antiiflammatory effects in WG and related diseases. Stenosis of the subglottic trachea (SGS) is a potentially life-threatening complication of WG that requires tracheostomy in up to 50% of cases. We developed a surgical technique for the management of SGS in patients with WG which combines mechanical dilatation of the subglottic trachea with injection of a long-acting glucocorticoid into the stenotic lesion. In 20 patients treated with this technique, none have required tracheostomy and 6 patients with previous tracheostomies were decannulated. Intratracheal dilation-injection therapy provides a safe and effective treatment modality for WG-associated SGS.